The overall goal of this PEN application is the development and imaging-facilitated evaluation of translational nanotechnology-based tools, and the development of associated multidisciplinary trainees, focused on the treatment of heart failure and atherosclerosis. We will apply nanotechnology to address the aforementioned cardiovascular diseases and integrate expertise in multiple disciplines, including vascular biology, tissue engineering, drug delivery, molecular biology, diagnostic imaging, chemistry, physics, bioengineering, and clinical sciences. Our multidisciplinary team includes investigators from Mount Sinai School of Medicine (MSSM), Massachusetts Institute of Technology (MIT), New York University (NYU), Columbia University (Columbia), and Brigham and Women's Hospital (BWH). Under the leadership of Zahi Fayad (MSSM) and Robert Langer (MIT), the application is structured to facilitate a synergistic interaction among the different investigators, to maximize clinical translation of the nanotechnology to biomedical and clinical problems, to optimize the design of nanotechnology components, and to train the next generation of engineers, scientists, and clinicians with the multidisciplinary skills to exploit nanotechnology towards eliminating the burdens of cardiovascular disease. The program consists of 3 innovative and translational research projects that utilize nanotechnology to tackle specific cardiac and vascular problems and thereby treat cardiovascular disease. Project 1 (Hajjar, Langer, Costa) will investigate minimally invasive nanotechnology-based approaches to deliver regeneration factors to the infarcted myocardium. In Project 2 (Fisher, Tabas, Langer, Farokhzad) novel nanotherapeutic approaches for defective inflammation resolution in atherosclerosis will be developed. Project 3 (Fayad, Mulder, Fuster, Langer) will develop a theranostic nanoparticle platform with surface activation properties to efficiently and specifically target and image macrophages in atherosclerotic plaques. All projects have a high degree of translational potential as well as a strong emphasis on developing state-of-the-art nanotechnology, with the balance between translation and technology varying among the 3 projects to create attractive and diverse platforms that are aligned with the overall goal of the NHLBI Programs of Excellence in Nanotechnology. Moreover, we chose to focus the different projects at two stages of cardiovascular disease, namely the (early) atherosclerotic inflammatory process and (late) myocardial regeneration after infarction. All 3 projects offer outstanding opportunities for the training and professional development of graduate students and postdoctoral fellows with the multidisciplinary skills required to apply nanotechnology in the context of cardiovascular disease.